- Email: [email protected]
Tinnitus-provoking salicylate treatment triggers social impairments in mice
Journal of Psychosomatic Research 67 (2009) 273 – 276
Short communication
Tinnitus-provoking salicylate treatment triggers social impairments in mice Matthieu J. Guitton⁎ Centre de Recherche Université Laval Robert-Giffard (CRULRG), Laval University, Quebec City, QC, Canada Faculty of Pharmacy, Laval University, Quebec City, QC, Canada Received 5 December 2007; received in revised form 1 May 2008; accepted 29 October 2008
Abstract Objectives: Tinnitus (perception of sound in silence) strongly affects the quality of life of sufferers. Tinnitus sufferers and their relatives frequently complain about major social impairments. However, it is not known whether this impairment directly results from the occurrence of tinnitus or is the indirect expression of a preexisting psychological vulnerability. Using the well-characterized animal model of salicylate-induced tinnitus, we investigate in mice whether the occurrence of tinnitus can trigger social impairments. Methods: Experiments were performed on 32 male Balb/C mice. Tinnitus was induced in mice using salicylate treatment. Social behavior was assessed in experimental and control animals using social interaction paradigm. Interaction time, number of social events, and number of nonsocial events
were assessed in all animals. Results: We demonstrate for the first time that treatment known to induce tinnitus triggers complex social impairments in mice. While salicylate-treated animals present a massive decrease in their overall social interactions compared to control untreated animals, they also display a paradoxal increase in the number of conspecific followings. Conclusion: Tinnitus can thus trigger a complex set of modifications of behavior, which will not only find their expression at the individual level, but also at the social level. Our results suggest that tinnitus can directly be a cause of psychosocial impairment in human and have strong implications for the clinical management of tinnitus sufferers. © 2009 Elsevier Inc. All rights reserved.
Keywords: Tinnitus; Social interactions; Social impairment; Salicylate
Introduction Tinnitus—the perception of sound in silence—chronically affects around 10% of the adult population and represents a major problem of public health in Western countries [1–4]. Tinnitus may strongly alter the quality of life of patients and can be a major cause of psychological suffering and social isolation for some patients [3,5,6]. Increase in anxiety-related symptoms, increase in stress perception and irritability, lowering of communication capabilities, and the following deterioration of social relations, both in the professional and familial life, are often observed by tinnitus sufferers and their relatives [3]. ⁎ Faculty of Pharmacy, Laval University, Quebec City, QC, Canada G1K 7P4. Tel.: +1 418 663 5747; fax: +1 418 663 8756. E-mail address: [email protected]. 0022-3999/08/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jpsychores.2008.10.017
Furthermore, several studies consistently report an elevated correlation between tinnitus and secondary symptoms, the most cited being sleep disturbance, irritability, depression, and anxiety [6–9]. However, it is unknown whether the social impairments observed in tinnitus sufferers are a consequence of tinnitus or the expression of a pre-required psychological condition [4]. In order to answer this question, we investigated whether the occurrence of tinnitus can produce social impairments in an animal model of salicylate-induced tinnitus. Salicylate—the active component of aspirin (acetylsalicylic acid)—is well known to induce tinnitus in humans [10,11] as well as in animals [12–16]. Here, we show that doses of salicylate classically used to induce tinnitus in animals [12,16] provoke significant alterations of social behavior in mice, which mimic what is observed in tinnitus sufferers.
274
M.J. Guitton / Journal of Psychosomatic Research 67 (2009) 273–276
Methods Animals Balb/C mice (males, 70±4 days old) were caged individually in the animal facilities of the Laval University Medical Centre at 22±1°C under a 12-h light/dark cycle regime. Water and food were available ad libitum. All experiments were approved by the Laval University Medical Centre Animal Care and Use Committee. Experimental protocol In order to determine whether tinnitus could trigger alterations of social behavior in mice, two groups of 16 animals were used. In the control group, all animals were naive and untreated. Animals were randomly paired to form eight couples. In the experimental group, half of the animals were untreated, while the second half received salicylate treatment. Animals receiving salicylate treatment were then paired with one of the related untreated animals, to form eight couples. Salicylate treatment consisted of a daily injection of saline containing sodium salicylate (300 mg/kg; Fluka, Steinheim, Germany) for four consecutive days. Injections were performed approximately at the same time everyday. Social interaction tests were performed at the fourth day of treatment, 2 h after the last injection of salicylate. This particular treatment is known to induce tinnitus in animals in a highly reliable manner [12–16]. The timeline of the social interaction behavioral testing (2 h after the last salicylate injection) was selected since it represents the moment when the perception of tinnitus should be at its peak [12,15].
wrestling, crawling over or under) [17]. Since social events can vary in duration (a sniffing being an almost instant event, while grooming the partner may be a longer event), the interaction time represents the total time spent in active behavior, regardless of the number of individual events. After each trial, animals were returned to their home cages and the arena was changed to a new and clean one, in order to avoid any odor cues from one couple to the next one. Statistical analysis Results are expressed as mean±S.E.M. Due to the size of the groups, nonparametric statistical analysis was preferred over parametric analysis. Thus, analyses were computed using Mann–Whitney U test for nonparametric data. Results At the group level, the time spent in active social interaction (interaction time) is higher for the control couples (couples formed by two untreated animals) than for the experimental couples (couples formed by one untreated animal and one animal treated with salicylate), although this difference is not significant (232.75±25.38 and 197.87±15.21 s for control
Social interaction paradigm Animals were submitted to a social interaction test, performed in a transparent plastic arena (40×22×18 cm). Pairs of age-matched animals, unfamiliar with each other, were placed in the unfamiliar test arena for an observation period of 20 min. Their social behavior and interaction time were then scored as follows. The number of behavioral events was quantified for each animal in the following categories: number of social events (sniffing, following, grooming the partner, crawling over or under), number of aggressive events (wrestling or biting), number of conspecific-following behavior (number of times the animal actively follows a moving partner in order to initiate or continue a social contact), number of conspecific-escapes (number of times the animal actively breaks the social contact by running away from a socially active partner), and number of grooming [17]. Each event consisted of a display of the given behavior and classically started with a physical contact and ended either when the physical contact finished or when the animal moved to the next behavior. The interaction time was defined as the time spent in active social interactions (sniffing, following, grooming the partner,
Fig. 1. (A) Number of social events displayed by animals from the control (untreated/untreated) and the experimental (untreated/salicylate-treated) couples during the 20-min test. (B) Number of conspecific-following displayed by animals from the control (untreated/untreated) and the experimental (untreated/salicylate-treated) couples during the 20-min test. White: untreated animals; gray: salicylate-treated animals. ***Pb.001.
M.J. Guitton / Journal of Psychosomatic Research 67 (2009) 273–276
Fig. 2. Number of conspecific-following behavior displayed by each of the two animals of the experimental couples (individual data). Gray: salicylatetreated animals; white: related untreated animals. Each column represents one couple (the order of presentation of the couple is arbitrary).
and experimental couples, respectively). However, major alterations of social behavior are easily evidenced in salicylate-treated animals. Indeed, while no difference was observed in the number of social events displayed by animals in the control couples (141.25±12.8 and 142.62±12.57), salicylate-treated animals presented a drastic decrease in the number of social events (84.12±6.58 and 139.62±11.51 social events, for salicylate-treated animals and related untreated animals, respectively, Pb.001; Fig. 1A). Interestingly, the number of social events is totally comparable across untreated animals, whether they belong to the control or to the experimental couples. In contrast, while the number of conspecific-followings remained stable across animals of the control group (0.25±0.16 and 0.37±0.26), this number was significantly increased in the experimental group for the salicylate-treated animals (4.62±0.59 and 0.25±0.16, for salicylate-treated animals and related untreated animals, respectively, Pb.001; Fig. 1B). Furthermore, in each of the couple tested, salicylate-treated animals displayed more behavior of following than related untreated partners (Fig. 2). No aggressive behavior (wrestling or biting), and almost no escape behavior, was observed, whatever the group. The only behavioral escapes were observed for two of the eight salicylate-treated animals (with only one and two escape events respectively for all the duration of the test). Finally, the number of grooming was not significantly affected by the salicylate treatment (4±0.71 and 3.5±0.59, for salicylatetreated animals and related untreated animals, respectively).
Discussion Using the well-characterized model of salicylate-induced tinnitus, we demonstrated here for the first time that the occurrence of tinnitus can provoke in animals alterations of social behavior which echo the social impairments observed in tinnitus sufferers.
275
Salicylate-treated animals presented a clear impairment of their social behavior, as assessed by the decrease in the interaction time between the control and the experimental couples, and by the lower number of social events displayed by salicylate animals when compared to the related untreated animals. However, salicylate-induced social impairments cannot merely just be described as a decrease in social interactions. Indeed, under tinnitus-inducing salicylatetreatment, animals displayed, along with a global decrease in social-related behavior, a paradoxal increase in the number of conspecific-following behavior. The social message carried by the behavioral cues was thus contrasted: salicylate-treated animals were seemingly willing to initiate social contact, but were not able to respond in an adequate manner. In other words, salicylate-treated animals seem to seek social contacts, but are obviously unable to maintain them once the interaction begins. A key issue is whether these social alterations are attributable to tinnitus or to other factors. The occurrence of nonauditory, unspecific effects of salicylate is, however, unlikely. Indeed, salicylate induces tinnitus through a specific activation of cochlear NMDA receptors [15,16]. Electrophysiological experiments strongly suggest that the abnormal neural signals that are erroneously interpreted as sound by the auditory centers are specifically propagated within the auditory system. Salicylate increases the spontaneous activity in the auditory nerve [18–20], in the inferior colliculus [21–23], as well as in the auditory cortex [24], but does not alter the spontaneous activity of cells recorded from nonauditory structures physically adjacent to the inferior colliculus, which argues against a nonspecific action of salicylate on the nervous system [21]. Another alternative possibility would be that salicylate treatment impaired locomotor activity. Again, this is unlikely, since injections of cyclooxygenase inhibitors are usually not reported to have massive locomotor side-effects [25,26]. Furthermore, the number of grooming (a socially independent locomotor behavior) measured during the 20-min test period was slightly higher for salicylate-treated animals than for related controls. Repeated salicylate injections failed to induce an anxietylinked escape behavior in a sensitive active avoidance paradigm in rats, when animals were tested 2 h after the last injection [15]. However, salicylate treatment may still constitute a putative stressor. Furthermore, tinnitus itself can generate anxiety [4]. Thus, the behavioral modifications observed in experimental animals may have an anxiety component, as complex alterations of social behavior in human tinnitus sufferers may be linked to an increase in anxiety levels [4]. However, the alterations of social behavior observed in experimental animals cannot be solely due to an increase in anxiety levels. Indeed, anxiety would be expected to produce a decrease in the number of following and a concomitant increase in the number of escape behaviors, none of them being observed in salicylatetreated animals.
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M.J. Guitton / Journal of Psychosomatic Research 67 (2009) 273–276
Tinnitus sufferers very commonly present alterations of their global psychological profile [5]. Interestingly, the social impairments observed in salicylate-treated animals are very similar to what is observed in human tinnitus sufferers. Specifically, the complex alterations of social behavior displayed by salicylate-treated mice strongly echo the social alterations described in numerous tinnitus sufferers [27]. Social interactions in humans are very complex. However, in line with what was observed during our experiments with salicylate-treated animals, tinnitus sufferers consistently selfreport difficulties in maintaining normal social interactions in everyday life situations [3]. In conclusion, our results support the idea that psychosocial impairments observed in human tinnitus sufferers should not be underestimated, but should be fully considered as part of the tinnitus pathology. This implies that this psychosocial dimension should be taken into consideration by public health systems when dealing with the clinical treatment of tinnitus sufferers. Acknowledgments The author thanks the Banting Research Foundation (Toronto, Canada) for financial support, and Dr Frédéric Calon and Carl Julien for helpful comments during the redaction of the manuscript. References [1] Coles R. Epidemiology of tinnitus: (1) Prevalence. In: Shulman A, editor. Proceedings of the 2nd International Tinnitus Seminar. New York: Raven Press, 1983. p. 7–16. [2] Goebel G. Fortschritte bei der verhaltensmedizinischen Diagnostik und Behandlung quälender chronischer Ohrgeräusche. Otorhinolaryngol Nova 1995;5:178–89. [3] Nicolas-Puel C, Lloyd Faulconbridge R, Guitton MJ, Puel JL, Mondain M, Uziel A. Characteristics of tinnitus and etiology of associated hearing loss: a study of 123 patients. Int Tinnitus J 2002;8: 37–44. [4] Guitton MJ. Tinnitus and anxiety: more than meet the ears. Curr Psychiatry Rev 2006;2:333–8. [5] Meric C, Gartner M, Collet L, Chéry-Croze S. Psychopathological profile of tinnitus sufferers: evidence concerning the relationship between tinnitus features and impact on life. Audiol Neurootol 1998;3:240–52. [6] Halford JB, Anderson SD. Anxiety and depression in tinnitus sufferers. J Psychosom Res 1991;35:383–90. [7] Dineen R, Doyle J, Bench J. Audiological and psychological characteristics of a group of tinnitus sufferers, prior to tinnitus management training. Br J Audiol 1997;31:27–38.
[8] Erlandsson SI, Rubinstein B, Axelsson A, Carlsson SG. Psychological dimensions in patients with disabling tinnitus and craniomandibular disorders. Br J Audiol 1991;25:15–24. [9] Schneider WR, Hilk A, Franzen U. Social support disability, coping with stress and personality markers in patients with subjective chronic aural tinnitus. HNO 1994;42:22–7. [10] McCabe PA, Dey FL. The effect of aspirin upon auditory sensitivity. Ann Otol Rhinol Laryngol 1965;74:312–24. [11] Myers E, Bernstein JM. Salicylate ototoxicity a clinical and experimental study. Arch Otolaryngol 1965;82:483–93. [12] Cazals Y. Auditory sensori-neural alterations induced by salicylate. Prog Neurobiol 2000;62:583–631. [13] Cazals Y, Horner KC, Huang ZW. Alterations in average spectrum of cochleoneural activity by long-term salicylate treatment in the guinea pig: a plausible index of tinnitus. J Neurophysiol 1998;80:2113–20. [14] Jastreboff PJ, Brennan JF, Coleman JK, Sasaki CT. Phantom auditory sensation in rats: an animal model for tinnitus. Behav Neurosci 1988; 102:811–22. [15] Guitton MJ, Caston J, Ruel J, Johnson RM, Pujol R, Puel JL. Salicylate induces tinnitus through cochlear NMDA receptors. J Neurosci 2003; 23:3944–52. [16] Guitton MJ, Pujol R, Puel JL. m-Chlorophenylpiperazine exacerbates perception of salicylate-induced tinnitus in rats. Eur J Neurosci 2005; 22:2675–8. [17] Salchner P, Lubec G, Singewald N. Decreased social interaction in aged rats may not reflect changes in anxiety-related behaviour. Behav Brain Res 2004;151:1–8. [18] Evans EF, Wilson JP, Borerwe TA. Animal models of tinnitus. Tinnitus, Ciba Foundation Symposium 85. London: Pitman, 1981. p. 108–38. [19] Evans EF, Borerwe TA. Ototoxic effects of salicylates on the responses of single cochlear nerve fibers and on cochlear potentials. Br J Audiol 1982;16:101–8. [20] Stypulkowski PH. Mechanisms of salicylate ototoxicity. Hear Res 1990;46:113–46. [21] Jastreboff PJ, Sasaki CT. Salicylate-induced changes in spontaneous activity of single units in the inferior colliculus of the guinea pig. J Acoust Soc Am 1986;80:1384–91. [22] Chen G, Jastreboff PJ. Salicylate-induced abnormal activity in the inferior colliculus of rats. Hear Res 1995;82:158–78. [23] Manabe Y, Yoshida S, Saito H, Oka H. Effects of lidocaine on salicylate-induced discharge of neurons in the inferior colliculus of the guinea pig. Hear Res 1997;103:192–8. [24] Ochi K, Eggermont JJ. Effects of salicylate on neural activity in cat primary auditory cortex. Hear Res 1996;95:63–76. [25] Jain NK, Patil CS, Kulkarni SK, Singh A. Modulatory role of cyclooxygenase inhibitors in aging- and scopolamine or lipopolysaccharide induced cognitive dysfunction in mice. Behav Brain Res 2002; 133:369–76. [26] Ross BM, Brooks RJ, Lee M, Kalasinsky KS, Vorce SP, Seeman M, Fletcher PJ, Turenne SD. Cyclooxygenase inhibitor modulation of dopamine related behaviours. Eur J Pharmacol 2002;450:141–51. [27] Bayar N, Oguzturk O, Koc C. Minnesota Multiphasic Personality Inventory profile of patients with subjective tinnitus. J Otolaryngol 2002;31:317–22.
Short communication
Tinnitus-provoking salicylate treatment triggers social impairments in mice Matthieu J. Guitton⁎ Centre de Recherche Université Laval Robert-Giffard (CRULRG), Laval University, Quebec City, QC, Canada Faculty of Pharmacy, Laval University, Quebec City, QC, Canada Received 5 December 2007; received in revised form 1 May 2008; accepted 29 October 2008
Abstract Objectives: Tinnitus (perception of sound in silence) strongly affects the quality of life of sufferers. Tinnitus sufferers and their relatives frequently complain about major social impairments. However, it is not known whether this impairment directly results from the occurrence of tinnitus or is the indirect expression of a preexisting psychological vulnerability. Using the well-characterized animal model of salicylate-induced tinnitus, we investigate in mice whether the occurrence of tinnitus can trigger social impairments. Methods: Experiments were performed on 32 male Balb/C mice. Tinnitus was induced in mice using salicylate treatment. Social behavior was assessed in experimental and control animals using social interaction paradigm. Interaction time, number of social events, and number of nonsocial events
were assessed in all animals. Results: We demonstrate for the first time that treatment known to induce tinnitus triggers complex social impairments in mice. While salicylate-treated animals present a massive decrease in their overall social interactions compared to control untreated animals, they also display a paradoxal increase in the number of conspecific followings. Conclusion: Tinnitus can thus trigger a complex set of modifications of behavior, which will not only find their expression at the individual level, but also at the social level. Our results suggest that tinnitus can directly be a cause of psychosocial impairment in human and have strong implications for the clinical management of tinnitus sufferers. © 2009 Elsevier Inc. All rights reserved.
Keywords: Tinnitus; Social interactions; Social impairment; Salicylate
Introduction Tinnitus—the perception of sound in silence—chronically affects around 10% of the adult population and represents a major problem of public health in Western countries [1–4]. Tinnitus may strongly alter the quality of life of patients and can be a major cause of psychological suffering and social isolation for some patients [3,5,6]. Increase in anxiety-related symptoms, increase in stress perception and irritability, lowering of communication capabilities, and the following deterioration of social relations, both in the professional and familial life, are often observed by tinnitus sufferers and their relatives [3]. ⁎ Faculty of Pharmacy, Laval University, Quebec City, QC, Canada G1K 7P4. Tel.: +1 418 663 5747; fax: +1 418 663 8756. E-mail address: [email protected]. 0022-3999/08/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jpsychores.2008.10.017
Furthermore, several studies consistently report an elevated correlation between tinnitus and secondary symptoms, the most cited being sleep disturbance, irritability, depression, and anxiety [6–9]. However, it is unknown whether the social impairments observed in tinnitus sufferers are a consequence of tinnitus or the expression of a pre-required psychological condition [4]. In order to answer this question, we investigated whether the occurrence of tinnitus can produce social impairments in an animal model of salicylate-induced tinnitus. Salicylate—the active component of aspirin (acetylsalicylic acid)—is well known to induce tinnitus in humans [10,11] as well as in animals [12–16]. Here, we show that doses of salicylate classically used to induce tinnitus in animals [12,16] provoke significant alterations of social behavior in mice, which mimic what is observed in tinnitus sufferers.
274
M.J. Guitton / Journal of Psychosomatic Research 67 (2009) 273–276
Methods Animals Balb/C mice (males, 70±4 days old) were caged individually in the animal facilities of the Laval University Medical Centre at 22±1°C under a 12-h light/dark cycle regime. Water and food were available ad libitum. All experiments were approved by the Laval University Medical Centre Animal Care and Use Committee. Experimental protocol In order to determine whether tinnitus could trigger alterations of social behavior in mice, two groups of 16 animals were used. In the control group, all animals were naive and untreated. Animals were randomly paired to form eight couples. In the experimental group, half of the animals were untreated, while the second half received salicylate treatment. Animals receiving salicylate treatment were then paired with one of the related untreated animals, to form eight couples. Salicylate treatment consisted of a daily injection of saline containing sodium salicylate (300 mg/kg; Fluka, Steinheim, Germany) for four consecutive days. Injections were performed approximately at the same time everyday. Social interaction tests were performed at the fourth day of treatment, 2 h after the last injection of salicylate. This particular treatment is known to induce tinnitus in animals in a highly reliable manner [12–16]. The timeline of the social interaction behavioral testing (2 h after the last salicylate injection) was selected since it represents the moment when the perception of tinnitus should be at its peak [12,15].
wrestling, crawling over or under) [17]. Since social events can vary in duration (a sniffing being an almost instant event, while grooming the partner may be a longer event), the interaction time represents the total time spent in active behavior, regardless of the number of individual events. After each trial, animals were returned to their home cages and the arena was changed to a new and clean one, in order to avoid any odor cues from one couple to the next one. Statistical analysis Results are expressed as mean±S.E.M. Due to the size of the groups, nonparametric statistical analysis was preferred over parametric analysis. Thus, analyses were computed using Mann–Whitney U test for nonparametric data. Results At the group level, the time spent in active social interaction (interaction time) is higher for the control couples (couples formed by two untreated animals) than for the experimental couples (couples formed by one untreated animal and one animal treated with salicylate), although this difference is not significant (232.75±25.38 and 197.87±15.21 s for control
Social interaction paradigm Animals were submitted to a social interaction test, performed in a transparent plastic arena (40×22×18 cm). Pairs of age-matched animals, unfamiliar with each other, were placed in the unfamiliar test arena for an observation period of 20 min. Their social behavior and interaction time were then scored as follows. The number of behavioral events was quantified for each animal in the following categories: number of social events (sniffing, following, grooming the partner, crawling over or under), number of aggressive events (wrestling or biting), number of conspecific-following behavior (number of times the animal actively follows a moving partner in order to initiate or continue a social contact), number of conspecific-escapes (number of times the animal actively breaks the social contact by running away from a socially active partner), and number of grooming [17]. Each event consisted of a display of the given behavior and classically started with a physical contact and ended either when the physical contact finished or when the animal moved to the next behavior. The interaction time was defined as the time spent in active social interactions (sniffing, following, grooming the partner,
Fig. 1. (A) Number of social events displayed by animals from the control (untreated/untreated) and the experimental (untreated/salicylate-treated) couples during the 20-min test. (B) Number of conspecific-following displayed by animals from the control (untreated/untreated) and the experimental (untreated/salicylate-treated) couples during the 20-min test. White: untreated animals; gray: salicylate-treated animals. ***Pb.001.
M.J. Guitton / Journal of Psychosomatic Research 67 (2009) 273–276
Fig. 2. Number of conspecific-following behavior displayed by each of the two animals of the experimental couples (individual data). Gray: salicylatetreated animals; white: related untreated animals. Each column represents one couple (the order of presentation of the couple is arbitrary).
and experimental couples, respectively). However, major alterations of social behavior are easily evidenced in salicylate-treated animals. Indeed, while no difference was observed in the number of social events displayed by animals in the control couples (141.25±12.8 and 142.62±12.57), salicylate-treated animals presented a drastic decrease in the number of social events (84.12±6.58 and 139.62±11.51 social events, for salicylate-treated animals and related untreated animals, respectively, Pb.001; Fig. 1A). Interestingly, the number of social events is totally comparable across untreated animals, whether they belong to the control or to the experimental couples. In contrast, while the number of conspecific-followings remained stable across animals of the control group (0.25±0.16 and 0.37±0.26), this number was significantly increased in the experimental group for the salicylate-treated animals (4.62±0.59 and 0.25±0.16, for salicylate-treated animals and related untreated animals, respectively, Pb.001; Fig. 1B). Furthermore, in each of the couple tested, salicylate-treated animals displayed more behavior of following than related untreated partners (Fig. 2). No aggressive behavior (wrestling or biting), and almost no escape behavior, was observed, whatever the group. The only behavioral escapes were observed for two of the eight salicylate-treated animals (with only one and two escape events respectively for all the duration of the test). Finally, the number of grooming was not significantly affected by the salicylate treatment (4±0.71 and 3.5±0.59, for salicylatetreated animals and related untreated animals, respectively).
Discussion Using the well-characterized model of salicylate-induced tinnitus, we demonstrated here for the first time that the occurrence of tinnitus can provoke in animals alterations of social behavior which echo the social impairments observed in tinnitus sufferers.
275
Salicylate-treated animals presented a clear impairment of their social behavior, as assessed by the decrease in the interaction time between the control and the experimental couples, and by the lower number of social events displayed by salicylate animals when compared to the related untreated animals. However, salicylate-induced social impairments cannot merely just be described as a decrease in social interactions. Indeed, under tinnitus-inducing salicylatetreatment, animals displayed, along with a global decrease in social-related behavior, a paradoxal increase in the number of conspecific-following behavior. The social message carried by the behavioral cues was thus contrasted: salicylate-treated animals were seemingly willing to initiate social contact, but were not able to respond in an adequate manner. In other words, salicylate-treated animals seem to seek social contacts, but are obviously unable to maintain them once the interaction begins. A key issue is whether these social alterations are attributable to tinnitus or to other factors. The occurrence of nonauditory, unspecific effects of salicylate is, however, unlikely. Indeed, salicylate induces tinnitus through a specific activation of cochlear NMDA receptors [15,16]. Electrophysiological experiments strongly suggest that the abnormal neural signals that are erroneously interpreted as sound by the auditory centers are specifically propagated within the auditory system. Salicylate increases the spontaneous activity in the auditory nerve [18–20], in the inferior colliculus [21–23], as well as in the auditory cortex [24], but does not alter the spontaneous activity of cells recorded from nonauditory structures physically adjacent to the inferior colliculus, which argues against a nonspecific action of salicylate on the nervous system [21]. Another alternative possibility would be that salicylate treatment impaired locomotor activity. Again, this is unlikely, since injections of cyclooxygenase inhibitors are usually not reported to have massive locomotor side-effects [25,26]. Furthermore, the number of grooming (a socially independent locomotor behavior) measured during the 20-min test period was slightly higher for salicylate-treated animals than for related controls. Repeated salicylate injections failed to induce an anxietylinked escape behavior in a sensitive active avoidance paradigm in rats, when animals were tested 2 h after the last injection [15]. However, salicylate treatment may still constitute a putative stressor. Furthermore, tinnitus itself can generate anxiety [4]. Thus, the behavioral modifications observed in experimental animals may have an anxiety component, as complex alterations of social behavior in human tinnitus sufferers may be linked to an increase in anxiety levels [4]. However, the alterations of social behavior observed in experimental animals cannot be solely due to an increase in anxiety levels. Indeed, anxiety would be expected to produce a decrease in the number of following and a concomitant increase in the number of escape behaviors, none of them being observed in salicylatetreated animals.
276
M.J. Guitton / Journal of Psychosomatic Research 67 (2009) 273–276
Tinnitus sufferers very commonly present alterations of their global psychological profile [5]. Interestingly, the social impairments observed in salicylate-treated animals are very similar to what is observed in human tinnitus sufferers. Specifically, the complex alterations of social behavior displayed by salicylate-treated mice strongly echo the social alterations described in numerous tinnitus sufferers [27]. Social interactions in humans are very complex. However, in line with what was observed during our experiments with salicylate-treated animals, tinnitus sufferers consistently selfreport difficulties in maintaining normal social interactions in everyday life situations [3]. In conclusion, our results support the idea that psychosocial impairments observed in human tinnitus sufferers should not be underestimated, but should be fully considered as part of the tinnitus pathology. This implies that this psychosocial dimension should be taken into consideration by public health systems when dealing with the clinical treatment of tinnitus sufferers. Acknowledgments The author thanks the Banting Research Foundation (Toronto, Canada) for financial support, and Dr Frédéric Calon and Carl Julien for helpful comments during the redaction of the manuscript. References [1] Coles R. Epidemiology of tinnitus: (1) Prevalence. In: Shulman A, editor. Proceedings of the 2nd International Tinnitus Seminar. New York: Raven Press, 1983. p. 7–16. [2] Goebel G. Fortschritte bei der verhaltensmedizinischen Diagnostik und Behandlung quälender chronischer Ohrgeräusche. Otorhinolaryngol Nova 1995;5:178–89. [3] Nicolas-Puel C, Lloyd Faulconbridge R, Guitton MJ, Puel JL, Mondain M, Uziel A. Characteristics of tinnitus and etiology of associated hearing loss: a study of 123 patients. Int Tinnitus J 2002;8: 37–44. [4] Guitton MJ. Tinnitus and anxiety: more than meet the ears. Curr Psychiatry Rev 2006;2:333–8. [5] Meric C, Gartner M, Collet L, Chéry-Croze S. Psychopathological profile of tinnitus sufferers: evidence concerning the relationship between tinnitus features and impact on life. Audiol Neurootol 1998;3:240–52. [6] Halford JB, Anderson SD. Anxiety and depression in tinnitus sufferers. J Psychosom Res 1991;35:383–90. [7] Dineen R, Doyle J, Bench J. Audiological and psychological characteristics of a group of tinnitus sufferers, prior to tinnitus management training. Br J Audiol 1997;31:27–38.
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